Notice Number - NOT-OD-09-058 Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Renewal Applications. Type 2 diabetes is characterized by impaired insulin action in tissues such as muscle, liver, and adipose tissue. Our long-term objective is to determine the mechanisms involved in the pathogenesis of insulin resistance and diabetes. We discovered that Retinol binding protein 4 (RBP4) is elevated in rodents and humans with obesity and insulin resistance. In studies funded by the Parent Grant, we demonstrated that chronic elevation of serum RBP4 levels causes insulin resistance in mice. Furthermore, lowering RBP4 levels improves insulin sensitivity in mice on a high fat diet. A major focus of the Parent Grant is to determine the physiologic, cellular, and molecular mechanisms by which RBP4 causes insulin resistance. Since submission of the Parent Grant, a high affinity receptor for RBP4 was identified - STRA6 (Stimulated by retinoic acid). STRA6 mediates retinol uptake into cells from retinol-RBP4. Our preliminary data demonstrate that STRA6 expression is increased in multiple skeletal muscles of insulin resistant obese mice. The overall goal of this Competitive Revision is to determine the importance of RBP4-STRA6 interactions in glucose homeostasis, insulin signaling, and retinoid biology in muscle. We hypothesize that elevated serum RBP4 levels cause insulin resistance in skeletal muscle in part through interactions of RBP4 with STRA6. To test this hypothesis, we put forth the following Specific Aim: To determine whether the interaction of RBP4 with STRA6 is an important mechanism underlying the insulin resistance that results from elevations in serum RBP4 levels. Subaims are: a. To determine the effects of altering STRA6 expression in muscle on glucose uptake and insulin sensitivity. b. To determine the effects of altering STRA6 expression in muscle on retinol uptake and metabolism. c. To establish a colony of skeletal muscle-specific STRA6 knockout mice and begin phenotypic characterization to determine whether these mice will be useful for future studies of the effects of STRA6 on insulin sensitivity. The proposed studies will enhance our understanding of the mechanisms by which elevated RBP4 causes insulin resistance in skeletal muscle and expand the scope of the Parent Grant since STRA6 is a novel pathway for RBP4 action. This could lead to new therapeutic targets to prevent or treat insulin resistance and type 2 diabetes. PUBLIC HEALTH RELEVANCE: Retinol binding protein 4 (RBP4) which carries vitamin A in the blood is elevated in serum of insulin resistant people with obesity and type 2 diabetes. This may contribute to the insulin resistance and risk for diabetes. We will investigate whether a recently discovered receptor for RBP4 plays a role in the development of insulin resistance.